Sex‐specific effect of prenatal alcohol exposure on N‐methyl‐D‐aspartate receptor function in orbitofrontal cortex pyramidal neurons of mice

Abstract

Background: Alcohol consumption during pregnancy can produce behavioral and cognitive deficits that persist into adulthood. These include impairments in executive functions, learning, planning, and cognitive flexibility. We have previously shown that moderate prenatal alcohol exposure (PAE) significantly impairs reversal learning, a measure of flexibility mediated across species by different brain areas that include the orbital frontal cortex (OFC). Reversal learning is likewise impaired by genetic or pharmacological inactivation of GluN2B subunit-containing N-methyl-D-aspartate receptors (NMDARs). In the current study, we tested the hypothesis that moderate PAE persistently alters the number and function of GluN2B subunit-containing NMDARs in OFC pyramidal neurons of adult mice. Methods:We used a rodent model of fetal alcohol spectrum disorders and left offspring undisturbed until adulthood. Using whole-cell, patch-clamp recordings, we assessed NMDAR function in slices from 90-to 100-day-old male and female PAE and control mice. Pharmacologically isolated NMDA receptor-mediated evoked excitatory postsynaptic currents (NMDA-eEPSCs) were recorded in the absence and presence of the GluN2B antagonist, Ro25-6981(1 µM). In a subset of littermates, we evaluated the level of GluN2B protein expression in the synaptic fraction using Western blotting technique. Results:Our results indicate that PAE females show significantly larger (~23%) NMDA-eEPSC amplitudes than controls, while PAE induced a significant decrease (~17%) in NMDA-eEPSC current density of pyramidal neurons recorded in slices from male mice. NMDA-eEPSC decay time was not affected in PAE-exposed mice from either sex. The contribution of GluN2B subunit-containing NMDARs to the eEPSCs was not significantly altered by PAE. Moreover, there were no significant changes in protein expression in the synaptic fraction of either PAE males or females.Conclusions: These findings suggest that low-to-moderate PAE modulates NMDAR function in pyramidal neurons in a sex-specific manner, although we did not find evidence that the effect is mediated by dysfunction of synaptic GluN2B subunitcontaining NMDARs.

Effects of developmental alcohol exposure on cortical multisensory integration

“…Therefore, potential contributors to MSI are the N ‐methyl‐ d ‐aspartate receptor (NMDAr) and γ‐aminobutyric acid receptor (GABAr). Interestingly, both can be affected by developmental alcohol exposure (Licheri et al, 2021; Savage et al, 1992; Smiley et al, 2015).…”

Sexually dimorphic organization of open field behavior following moderate prenatal alcohol exposure

“…Additionally, recent work has observed that moderate PAE influences the firing characteristics of spatially tuned hippocampal cells, such that the prominence of firing in relation to environmental position is reduced (Harvey et al, 2020). PAE can also induce structural and functional changes in other neural systems involved in spatial behavior including the medial septum (Moore et al, 1997), anterior cingulate cortex (Moore et al, 1998), and orbitofrontal cortex (Licheri et al, 2021). These changes in hippocampal, cortical, and subcortical function likely contribute to observed impairments in spatial information processing.…”

Long‐term effects of low prenatal alcohol exposure on GABAergic interneurons of the murine posterior parietal cortex

“…A separate cohort of 18 mice (4–5 animals for each experimental group) from eight SAC and eight PAE litters were used for electrophysiological studies. These mice had ad libitum access to food as previously described (Licheri et al., 2021) as food restriction in mice or rats can alter cortical GABAergic transmission (Dazzi et al., 2014; Yang et al., 2016). In all cases, the investigators were blind to the treatment group assignments.…”